Epilepsy is a set of disorders that result from neuronal hyperexcitability and hypersynchronous neuronal firing. Epilepsy remains a major widespread neurological concern. Current medications do not meet the health needs of 30% of epilepsy patients, and approximately 40% of patients experience serious side effects. So, the need for novel, more effective therapies is apparent. NeuroGate Therapeutics (NGT) has advanced a novel class of agents termed Extended NeuroAmides (ENAs), which have exhibited, in established animal seizure models, superb anticonvulsant activities comparable or better than most antiepileptic drugs. Recent studies have documented that the sodium channel slow inactivation (SI) state is a valid target for epilepsy. NGT has demonstrated that ENAs preferentially, potently, and stereospecifically transition Na+ channels into the SI state, and show frequency (use)-dependency. ENA Na+ channel SI activity far exceeded that of any reported anticonvulsant agent. These findings indicated that ENAs can reduce the pathological activity associated with neuronal hyperexcitability (sustained depolarization, high-frequency spiking) without significantly disrupting normal physiological activity. ENAs have shown no interactions with receptors known to adversely impact drug effectiveness. In this proposal, NGT requests funds to identify the optimal ENA that would permit investigational new drug (IND)-enabling studies in the STTR phase II grant. In Specific Aim 1, NGT will build upon an evolving structure-activity relationship study using synthesis, whole animal pharmacology that determines efficacy and neurotoxicity, and CAD cell patch-clamp electrophysiology to identify ENAs of interest. Four selected ENAs will be tested for CYP-450 inhibition and evaluated by electrophysiology using hippocampal cells. In Specific Aim 2, NGT will evaluate the two most promising ENAs in recombinant cell lines that express CNS Na+ channels (NaV1.1, NaV1.2, NaV1.3, NaV1.6) and cardiac NaV1.5 channel in order to gain information on mechanism of action and safety. In Specific Aim 3, NGT will evaluate the bioavailability in the rat of the most promising ENA and the utility of this ENA for treating pharmacoresistant epilepsy. Identifying an optimized ENA for the IND-enabling studies will permit NGT to advance a compound for clinical testing, with the support of phase II STTR funding. PUBLIC HEALTH RELEVANCE: Epilepsy is a serious neurological disorder that affects 1% of the world population and for which current medications are ineffective for 30% of patients. We have identified a new class of compounds, termed Extended NeuroAmides, that exhibit potent activities in established anticonvulsant animal models and that function by a unique mechanism of action. The proposed investigation provides a critical path for ENA development and selection allowing for IND- enabling studies in the STTR phase II study.